Indomethacin inhibits tetrodotoxin-resistant Na+ channels at acidic pH in rat nociceptive neurons

Non-steroidal anti-inflammatory drugs (NSAIDs) are well-known inhibitors of cyclooxygenases (COXs) and are widely used for the treatment of inflammatory pain; however several NSAIDs display COX-independent analgesic action including the inhibition of voltage-gated Na+ channels expressed in primary afferent neurons. In the present study, we examined whether NSAIDs modulate tetrodotoxin-resistant (TTX-R) Na+ channels and if this modulation depends on the extracellular pH. The TTX-R Na+ currents were recorded from small-sized trigeminal ganglion neurons by using a whole-cell patch clamp technique. Among eight NSAIDs tested in this study, several drugs, including aspirin and ibuprofen, did not affect TTX-R Na+ channels either at pH 7.4 or at pH 6.0. However, we found that indomethacin, and, to a lesser extent, ibuprofen and naproxen potently inhibited the peak amplitude of TTX-R Na+ currents at pH 6.0. The indomethacin-induced inhibition of TTX-R Na+ channels was more potent at depolarized membrane potentials. Indomethacin significantly shifted both the voltage-activation and voltage-inactivation relationships to depolarizing potentials at pH 6.0. Indomethacin accelerated the development of inactivation and retarded the recovery from inactivation of TTX-R Na+ channels at pH 6.0. Given that indomethacin and several other NSAIDs could further suppress local nociceptive signals by inhibiting TTX-R Na+ channels at an acidic pH in addition to the classical COX inhibition, these drugs could be particularly useful for the treatment of inflammatory pain. •Indomethacin potently inhibited TTX-R Na+ channels at pH 6.0.•Indomethacin shifted voltage-dependence for activation and inactivation of TTX-R Na+ channels at acidic pH.•Indomethacin changed the inactivation kinetics of TTX-R Na+ channels at pH 6.0.